In the pharmaceutical industry, oral administration of drugs is regarded as the most advantageous form for drug delivery. There are two major types of orally administered drug dosage forms, i.e., granules (which can be packaged into a capsule) and tablets, both are also frequently employed in non-pharmaceutical field such as fish foods, plant growth regulators, pesticides, herbicides and the like.
The simplest and most economical procedures for the manufacturing of granules and tablets are the direct grinding, granulation, and compression of all the ingredients distributed homogeneously. Usually, in addition to the blending of one or more active ingredients, at least one pharmaceutical excipient, such as a diluent, a filler, a binder, a disintegrant, a lubricant, etc., is required. An excipient is an inert and non-toxic substance added to the granules or tablets to confer a suitable consistency or form to the drug(s).
Diluents or fillers are added to increase bulk to the formulation. Lubricants are added to reduce friction during the tabletting process.
Binders are useful for grinding, granulating and/or tabletting some pharmaceutical ingredients. They provide the cohesiveness necessary for bonding together the ingredients in granules or compressing granules into tablets. Binders are especially useful in manufacturing tablets. They increase the strength of the compressed tablets and decrease the friability, leading to an improvement in the tablet appearance and mechanical characteristics. An appropriate binding agent shows flowing properties and can be blended easily.
Conventional binders include microcrystalline cellulose (Avicel PH101® and Avicel PH102®), polyvinylpyrrolidone (Kollidon®, Plasdone®), corn starch, modified starches, gums, etc. These binders are usually employed in direct compression at a concentration level of about 20% by weight. The quantity of binder used in a formulation must be carefully regulated, particularly since the tablets must disintegrate after oral administration to liberate the drug.
Disintegrants are usually added to cause the granules or compressed tablets to break immediately apart when placed in an aqueous medium. Typical disintegrants include gelatinized starches (Sta Rx®) or modified starches such as sodium starch glycolate (Primojel®). Some of these disintegrants are given the name of “superdisintegrants” because of their high efficiency, even at low concentration, and because of their high swelling capacity in the presence of water, possibly due to capillarity effect upon encounter with water.
It is known that some excipients, such as microcrystalline cellulose, present binding and disintegrating characteristics and therefore are useful both as a binder and a disintegrant.
Di- and polysaccharides, such as starch, cellulose, lactose, maltose, and sugar, are well-known to fulfil several granulation and tabletting functions, particularly as the combination of binder and filler, or binder and disintegrant. In particular, the starch products are known to be suitable in the manufacture of tablets by direct compression, whereby the powder mixture to be tabletted is introduced into the molds of a tabletting press and then compressed into tablets. For example, G. H. P. Te Wierik et al., Pharmaceutical Research, (1993), 10: 1274-1279, teach the preparation and use of linear dextrins, amylodextrin, metastable amylodextrins, and metastable amylose as tabletting excipients. International patent publication WO 94/01092 describes the use of low-molecular or high-molecular amylose products as tabletting excipients.
Most kinds of starch consist of granules in which two types of glucose polymers occur, i.e., amylose and amylopectin. Amylose is the unbranched type of starch that consists of glucose residues in α-1,4 linkage with an average degree of polymerization of 1000-5000 (depending on the kind of starch). Amylopectin is the branched form of starch which consists of one a α-1,6-linkage per thirty α-1,4 linkages with an average degree of polymerization of about 2,000,000. The commercially most important types of starch, i.e., corn starch, potato starch, wheat starch, and tapioca starch, contain 15-30% by weight of amylose. Of some types of cereal (barley, corn, millet, milo, rice and sorghum) and of potato starch, there exist varieties that consist substantially and completely of amylopectin. These types of starch contain less than 5% by weight of amylose and are designed by the term amylopectin starches.
Cellulose is an unbranched polymer of glucose residue joined by β-1,4-linkages. Cellulose is also well-known as a binder/disintegrant in the pharmaceutical industry. For example, U.S. Pat. Nos. 2,978,446, 3,141,875, and 3,023,104 to Battista disclose a microcrystalline form of cellulose where crystalline cellulosic aggregates are prepared in an acid medium. This product is presently sold under the tradmark of Avicel PH101® and Avicel PH102®.
Chitosan is another polysaccharide composed of repeating glucosamine units that are obtained by de-acetylation of chitin. Chitin can be obtained from exoskeletons of insects and crustacea. Chitin consists of N-acetylglucosamine in β-1,4 linkage. Thus, chitin is like cellulose except that the substituent at C-2 is an acetylated amino group rather than a hydroxyl group. Chitosan is also well-known as a binder/disintegrant.
However, in preparing either the starch or the cellulose excipients, it is a necessary step to add solvent(s) to the excipients, especially for preparing binders and disintegrants. Although the majority of the solvents are removed at the end of the preparation, a significant amount of solvents is still remained in the excipients. These residual solvents, if used in daily drug dosages for patients, may constitute a threat to and create negative effect on human health and safety.
The invention to be presented in the following sections introduces low-residual-solvent-containing (<3000 ppm) excipients and a method for preparing such low-residual-solvent-containing excipients. The low-residual-solvent-containing excipients are obtained by linking a water absorbing radical to the free carbinol group(s) on the excipients to improve the water absorbing properties of the excipients so as to replace the residual solvent with water.